Thursday, 28 February 2019

Question: "Is maternal use of prenatal vitamins associated with decreased risk for autism recurrence in siblings of children with autism spectrum disorder?" Answer: "Maternal prenatal vitamin intake during the first month of pregnancy may reduce ASD [autism spectrum disorder] recurrence in siblings of children with ASD in high-risk families." So that looks like a 'very possibly' then.

The Schmidt study on this occasion relied on data from the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) study, an important longitudinal initiative originally designed to investigate "possible pre-natal and post-partum biological and environmental exposures and risk factors that may contribute to the development of autism." Yes, you read that right, that's 'biological and environmental' exposures and risk factors (see here)...

In this "prospective cohort study" younger brothers and sisters deemed to be at high-risk of autism (N=241) by virtue of their older sibling having been diagnosed with autism were the target participant group. Said group were followed from 6 months to around about their third birthday and developmentally assessed. Mums of the children were also asked about their vitamin use during pregnancy via interview. All the collected data was crunched and results presented.

"The prevalence of ASD was 14.1% (18) in children whose mothers took prenatal vitamins in the first month of pregnancy compared with 32.7% (37) in children whose mothers did not take prenatal vitamins during that time." As you can see, that is quite a stark [statistically significant] difference between the groups bearing in mind that around 25% of the total cohort were eventually diagnosed with autism (or at least met thresholds for a diagnosis based on the use of a gold-standard instrument). Authors also add that prenatal vitamin use did not seemingly impact on "other nontypical development" which included various other developmental 'outcomes'. They also reported that: "Children in the former maternal prenatal vitamin group also had statistically significantly lower autism symptom severity... and higher cognitive scores." This implies that even if such vitamin use did not 'halt' a/the pathway to an autism diagnosis in some, it might well have affected the presentation of their autism in terms of symptoms and intellectual functions (see here).

So an important question: what were the nutrients being supplemented that seemed to show such an effect? Well, as per that other previous research from Schmidt et alfolic acid popped up again, as well as another important nutrient, iron (Fe) which she's also been previously interested in (see here).

As per some 'expert reaction' to the study (see here) there is a need for further research in this area before any sweeping generalisations are made. Ideally, I'd like to see Schmidt or others go further into the whole folate metabolism bit applied to autism (see here and see here) and what that means for supplementation levels in mums-to-be where offspring autism recurrence risk is potentially high. Indeed, whether folic acid is actually the ideal supplement for some pregnant mums (see here) is another potential route of investigation on the basis of what has previously turned up in 'some autism' (see here). By saying all that, I want to make it clear that I'm not giving anything that looks, sounds or smells like medical or clinical advice on this or any topic. The Schmidt findings also potentially tie into another area of autism research looking at the inter-pregnancy interval (IPI) with autism in mind (see here and see here). This, on the basis that words like 'depletion of micronutrients' have been banded around as being one possible explanation for the elevated risk of offspring autism correlating with a short IPI. Again, more study is indicated.

I try not to get too excited about new findings when it comes to autism because, inevitably, many end up falling by the wayside or being over-hyped. Given however the history of peer-reviewed science on the topic of pregnancy nutrition and risk of offspring autism, I'm inclined to think that there may be something quite special in the Schmidt findings and what directions they could eventually take with regards to both research and policy. Certainly when I read another study talking about siblings at 'high-risk' for autism, I'll be looking to see whether pregnancy nutrition has been considered as a potentially modifying variable...

28 February 2019: An addition. So, here I am talking about prenatal vitamin use and offspring autism risk and lo-and-behold, someone has just published a meta-analysis and systematic review of this topic [2]. The conclusion: "the likelihood of ASD in offspring whose mothers used multivitamin supplements during the prenatal period was significantly reduced compared with that in offspring of mothers without such supplementation."

It's based on a study of over 28,000 adolescents here in Blighty: "51.2% of whom were in Year 7 (age 11–12) and 48.8% of whom were in Year 9 (age 13–14) in 97 state-maintained secondary schools across six geographical locations in England."

Said young people were given the "child self-report Strengths and Difficulties Questionnaire (SDQ)" to complete, and the received data were analysed alongside other information collected by the authors "from the National Pupil Database: SEN status; FSM eligibility; child in need status (CIN, this is a child who either (a) is unlikely to achieve/maintain a reasonable standard of health and development without local authority provision; (b) is likely to be impaired without local authority provision; or (c) is disabled); and ethnicity (Asian, Black, Chinese, Mixed, White or any other ethnic group)."

In more detail: "18.4% scored above the abnormal threshold for emotional symptoms, 18.5% for conduct problems, 25.3% for inattention/hyperactivity and 7.3% for peer-relationship problems." Going back to the title of this post, researchers mention how "around two in five young people scoring above ‘abnormal’ thresholds for three of the four problem areas measured (emotional problems, conduct problems and hyperactivity)." They also observed that:

SEN - special educational needs - status played a role in those figures (those with SEN were consistently more likely to provide an above-threshold response to all the areas measured, particularly peer-relationship problems).

Entitlement to free school meals (FSM), a potential marker of deprivation, was also associated with an above-threshold response to all areas.

There are caveats attached to the Deighton findings; not least the sole reliance on "child self-report data from a very brief assessment tool" without any accompanying further analysis on the presence (or not) of diagnosable psychopathology. But, in the context of the large participant number included for study and that most adolescents aren't likely to 'lie' about their positive responses to items such as "I get very angry and often lose my temper" or "I take things that are not mine from home, school or elsewhere" I'd be inclined to view the Deighton findings as a pretty accurate representation of their 'in the thousands' cohort.

So where next? Well, if we're talking about findings observing that "42.5% scored above threshold for any one of the first three problem scales (emotional symptoms, conduct problems or inattention/hyperactivity)" we have to talk about what services are in place (and should be in place) to support this large group. This, on the basis that, such 'problems' can potentially lead to various other 'adverse' outcomes both in later childhood and beyond. And when I talk about 'support', I mean both support and intervention to help those young adults to manage such issues. All of this set in the context of a continually squeezed financial and resource position (at least here in Blighty).

The other question has to be 'why'? Why have so many young people reported as they have? Deighton et al talk about various factors as potentially being important: "the impact of austerity, increasing experience of academic pressures, reduced rates of sleep and increased use of social media", to a large extent talking about the social environment as playing a significant role. I don't doubt that these external factors and other related variables will play a role in how young people are reporting, but I'm not convinced that the social environment is the only important factor to consider. It's not, for example, beyond the realms of possibility that other genetic and non-genetic variables (i.e. in the physical environment) could also play a role; something I say in the context of a 'growth' in the number of children and young adults being diagnosed with all-manner of different behavioural and/or psychiatric labels (see here and see here for examples).

Something important seems to be going on with our young people (see here and see here). We have to assume that such an issue is not going to resolve itself and may even increase in terms of numbers as time goes on. We really need to find out what factors are behind this and start taking action... like now.

On this most recent publishing occasion, Chu et al set out to: "Describe ME/CFS onset and course in one United States-based cohort." They did this via the use of "a detailed survey" that asked various questions about the first stages of participants' illness and what this eventually led to. The results obtained weren't exactly unexpected, but yet again stress how lots of things 'assumed' about ME/CFS really need to be properly verbalised in the peer-reviewed science literature (see here and see here for other examples). Of particular note in the Chu findings pertinent to inquiry on the 'course' of ME/CFS is this important snippet of information: "Based on available data, the median age of illness onset was 36.6 ± 12.3 years and median duration of illness was 12.5 ± 10.1 years." That's 'median duration of illness was 12.5± 10.1 years'.

Results: "The most common peri-onset events reported by subjects were infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%)." Infection or rather 'infection-related episodes' came out top of the pops with regards to possible onset events. I've said 'possible onset events' in that last sentence not to be belittle the first-hand reports obtained, but rather to emphasise how we're still in a bit of a 'not knowing' state when it comes to definite causative infective agents and ME/CFS onset. Yes, there is some quite strong evidence that infections caused as a result of Epstein–Barr virus (EBV) seem to be involved in some cases of ME/CFS (see here) but more often that not, people aren't screened for every possible viral or bacterial agent. At this point, I'd also hark back to the viral 'hit-and-run' hypothesis that has been talked about in some ME/CFS circles recently (see here and see here) and what this also means.

Onward: "For the overwhelming majority of patients (96%, n = 141), their illness did not improve with time although different patterns of illness were seen." That last sentence really speaks for itself in terms of what ME/CFS means in the long-term. That's not to say that symptoms did not 'fluctuate' - "59%, fluctuating (symptoms could change in severity but were always present)" - but participants on the whole did not 'shake off' their disability. And when it came to some details about how symptoms ebbed and flowed over the course of time, Chu et al have some data on that too: "Over time, flu-like symptoms, fatigue, unrefreshing sleep, and exertion-related items decreased the most, by between 12 and 25%... Cognitive symptoms present at the beginning of the illness tended to persist, declining by only 4–10%." Further focus on 'cognitive symptoms' is perhaps important [3].

Further: "Ninety-seven percent suffered from at least one other illness: anxiety (48%), depression (43%), fibromyalgia (39%), irritable bowel syndrome (38%), and migraine headaches (37%) were the most diagnosed conditions." The authors phrase this in the context that "patients with co-morbid medical or psychiatric conditions are the rule rather than the exception" when it comes to ME/CFS. But just before anyone starts making noises that anxiety and depression are so significantly present in this cohort and probably beyond, such findings does not open the door to any psychobabble 'biopsychosocial' (BPS) explanations about the cause/perpetuation of ME/CFS. I think many patients (and researchers) have had quite enough of all that (see here).

The Chu paper is a comprehensive one and adds to our knowledge about ME/CFS. It has its limitations - "reliance on subject self-report, recall bias, and relative superficiality of some survey items" - but no more or less than lots of other ME/CFS research. It hopefully will open the door to a lot more similar study; perhaps also including the odd biological measure also.

And just before you go, I'll draw your attention to the findings reported by Katherine Rowe [4] who also asked a cohort of participants with ME/CFS about their illness experiences. There's a few important matching details included in the paper - "Eighty percent reported a defined onset following an infection" - but also some other noteworthy information. One such observation was that: "Many indicated the need to be sensitive about when psychological assistance is offered... They were sensitive as to whether this was implying that psychological issues were the “cause.”." It's not difficult to see why patients with ME/CFS would think such [BPS] things.

Monday, 25 February 2019

I'm heading off-piste with my musings today, drawing your attention to a paper by Anthony Pelosi [1] and an accompanying editorial by David Marks [2] (both open-access) that are likely to 'put the cat among the pigeons' in some quarters (with thanks to Matthew Dalby for bringing the Pelosi study to my Twitter attention). Indeed, the publishing journal - The Journal of Health Psychology - is no stranger to 'cat among the pigeons' discussions, as per their 2017 special edition [3] on the PACE trial "for patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)." Perhaps interestingly, there is a 'psychosomatic' connection between the topic covered in the Pelosi paper and those critical musings on how to (or perhaps how not to) treat ME/CFS...

The person at the centre of the Pelosi paper is the late Prof. Hans Eysenck; a figure who anyone with the slightest interest in the discipline called psychology would probably have heard of. Personality was one of the major research interests for Eysenck, and in particular, the proposal of dimensions to personality: extroversion/introversion, neuroticism/stability, psychoticism/socialisation. Perhaps not as famously known about, but still influential, were Eysenck's views relating to "his persistent denial of the carcinogenic effects of tobacco." Indeed, his 'alternative view' that "certain personality traits that lead to smoking also increase the risk of developing cancer" is starting to look decidedly 'shaky' in modern times. More so when there is talk of 'funding' and 'sources of funding' potentially complicating the issue.

Pelosi (and Marks) make a case that the time is right for psychology and various other interconnected disciplines to start looking more critically at the collected published work of Eysenck and some of his colleagues. They argue that claims "about the alleged effectiveness of psychotherapy in preventing cancer" or that "behaviour therapy may be useful in prolonging life, as well as in preventing disease" have little place in modern, evidence-based, science and medicine. Pelosi - who has some important history of being slightly critical of some of Eysenck's findings alongside other notable names - also goes one stage further in suggesting that some of the "widely cited studies" published with Eysenck's name attached "have had direct and indirect influences on some people’s smoking and lifestyle choices." Further: "This means that for an unknown and unknowable number of individual men and women, this programme of research has been a contributory factor in premature illness and death." Strong words indeed.

Marks ends his editorial with open letters to the President and Principal of King's College London and the Chief Executive of the British Psychological Society (BPS) calling for further investigation of the points highlighted in the Pelosi paper. Pelosi has seemingly approached the BPS previously on this matter but apparently did not receive a particularly warm reception to his then request for further investigation of some of the science and conclusions made in this area (see here). Whether such a second request - made in the era of social media - will be acted upon differently this time is a 'wait and see' question. All of this taking into account the moves being made to make psychology a more credible science these days...

Saturday, 23 February 2019

I have to admit that I've always been a little bit bewildered by the use of the zebrafish (Danio rerio) in autism research. It's not that I don't understand the [careful] use of 'animal models' for autism research, or that zebrafish make for good research model material [1] from a genetic and biological point of view. It's just that zebrafish seem so far removed from real life autism; it's heterogeneity, complexity and also its 'humanness'.

The findings published by David James and colleagues [2] kinda changed my mind a little bit. Their findings supporting "mutations in SHANK3 as causal for GI [gastrointestinal] transit and motility abnormalities" caught my attention. Even more so when I realised that this was not the first time that I've blogged about SHANK3 disruptions having more than just 'brain effects' (see here), their connection to the gut (intestinal barrier function no less) and what this could mean for some autism.

I can't really claim any major expertise in the hows-and-whys of genetically manipulating zebrafish to "generate a zebrafish model of PMS [Phelan-McDermid syndrome]... a condition caused by mutations in the SHANK3 gene" but it was nonetheless achieved. I understand that the technique known as CRISPR/Cas9 was utilised as part of the research strategy and led to the production of mice with "shank3 loss-of-function mutations." Researchers subsequently set about studying their SHANK3 mutant zebrafish specifically focused on "the digestive tract (DT) structure and function." To do this we are told that "videos of gut peristalsis in intact transparent 7-day-old zebrafish larvae after feeding with a chicken egg yolk emulsion" were captured. Peristalsis by the way, refers to the waves generated by muscle movement that, in the gut, keep things moving from top to bottom. Researchers also fed microscopic "fluorescent beads" to mutant and non-mutant (wild type) zebrafish larvae in order to measure digestive tract (DT) transit as a function of that SHANK3 dysregulation. A few other experiments were also carried out and reported on pertinent to their research focus.

"Our studies are the first to establish DT dysmotility as a robust phenotype in any SHANK3 mutant animal model of ASD [autism spectrum disorder]." Hypomobility denoting a reduction in gut motility was found, something that perhaps ties in with other more general autism-related research literature (see here). The magnitude of the reduced gut motility reported by James and colleagues was quite notable: "Comparatively, shank3abΔC +/− larvae took longer than 12 h to begin passing the microspheres and some individuals had not passed the remainder even after 24 h post consumption." Authors talk about 'sloshing' as being potentially important to this increased transit time "where the microspheres would repeatedly move anteriorly and posteriorly between the intestinal bulb and upper-intestine."

Another detail mentioned by James et al relates to their attempt to "rescue the DT dysmotility phenotype" via an injection of "mRNA encoding either the longest human SHANK3 isoform that includes all SHANK3 protein domains (5t, n = 19) or a shorter human SHANK3 isoform that includes only the C-terminal proline-rich and SAM domains (32t, n = 6) into fertilized eggs from shank3abΔC +/− mutants." This 'we can rebuild him' molecular rescue attempt wasn't a complete success, although did partially improve the DT (digestive tract) transit time.

OK, so one needs to remember that this is still work based on the examination of zebrafish. It's work that looked at one particular genetic 'issue' noted in a genetic condition that manifests behaviour(s) that look like autism [3]. There are, as you can see, various issues that perhaps stand in the way of making any sweeping generalisations back to 'all autism'. But in light of the other research in this area similarly linking gut-related parameters back to SHANK3 disruptions, a trend is beginning to appear. A trend that taps into other important concepts in autism research that "brain, gut, and microbiome" represent emerging research areas with respect to autism, that 'autism genes are probably not just genes for autism' in a brain-behaviour sense (see here) and onward that gastrointestinal (GI) issues appearing alongside autism may be much more than just 'comorbidity' for some...

The scale of the issue facing the various health and social care trusts when it comes to the significant 'growth' in both received and 'awaited' autism diagnoses is not to be under-estimated. Indeed, the BBC really needn't have gone down the FOI route because Northern Ireland already collects and quite publicly publishes quite a lot of information about autism in children under their geographical jurisdiction (see here and see here).

The details? Well, if you ever you needed proof that autism is still on the increase among children and young adults, the data provide it: "In total 2,345 children under 18 were diagnosed as autistic last year, compared with 1,047 five years previously." And other details are important too: "In keeping with trends that show males are more likely to be diagnosed, almost three times more boys than girls were found to be autistic in the five years."

What else is there to say? Some old and tired arguments about 'increasing autism awareness' being behind the increase in cases being diagnosed (and awaiting diagnosis and/or assessment) is reported in the BBC piece. About 20 years ago I would have agreed with this but not so much now; we are in an age of autism awareness and have been for several years. Perhaps it's time to start thinking about what factors outside of awareness might also be contributing to the substantial increase? Y'know, entertain the idea that some of the increase may well be a real increase (see here) and start thinking about what factors might be important there?

And with growing numbers of children and young adults being diagnosed with autism, so more current- and future-planning is required to ensure that their health, educational and social needs are met. It sounds great in theory but the reality is that service provisions and resources are already struggling and increasingly scarce. Indeed, a recent article on autism from across the Pond titled "The Coming Care Crisis as Kids With Autism Grow Up" hits the nail right on the head about how 'strained' many systems currently are. And that's without even taking into account what's going to happen 5 or 10 years down the line when more and more autistic children turn into autistic adults. Action is required, like now.

Thursday, 21 February 2019

I appreciate that the findings reported by Mary Ajamian and colleagues [1] probably aren't going to set many research hearts racing. Their observations that "current commercial zonulin assays are not detecting the actual protein as prehaptoglobin-2" is not exactly 'change the world' science, but that doesn't mean that they aren't important findings.

So, zonulin is the name of the research game. A protein described with properties "capable of reversible tight junction disassembly and, therefore, is implicated in the regulation of mucosal permeability" means that zonulin and dysregulation of the zonulin pathway has found a home in the science of 'gut permeability' a.k.a leaky gut. And it is with mention of the misnomer called 'leaky gut' and it's *association* with some autism (see here) that I gravitated towards the Ajamian findings. Indeed, zonulin has already made a mark in autism research too (see here). We'll come back to this shortly.

Researchers zoomed in on some of the commercially available methods currently available to 'test for zonulin' - "commercially-available ELISA assays" - and whether they are cutting the scientific mustard. And before I go on I should mention that Ajamian et alaren't the only ones who have looked at this issue [2]. Two ELISA assays were examined: "from CUSABIO (Wuhan, China) and Immundiagnostik AG (Bensheim, Germany)" and pitted against each other and various other analytical techniques to assess "whether the assays are reliably detecting zonulin as prehaptoglobin-2 and if not, what they may be detecting instead." I note the words 'mass spectrometric analysis' are also used in the Ajamian paper, which is music to my analytical ears.

Results: "Serum samples were collected from well-characterised patients and healthy individuals between the ages of 16 and 70 years living in Melbourne, Australia." Those 'well-characterised' participants included those diagnosed with non-coeliac wheat sensitivity (NCWS), coeliac disease, and ulcerative colitis (N=93) and their results were compared with nearly 50 asymptomatic controls. "The majority of study participants were zonulin-producers" as haptoglobin phenotype (see here) was also described in the Ajamian study.

Then to the serum [purported] zonulin levels as measured by those commercial assays: "Compared with the cohort of healthy individuals with a median (IQR) of 0.00 (0.00) ng/mL, patient median (IQR) values for purported zonulin were elevated (all p<0.0001) at levels of 0.032 (0.90) ng/mL in NCWS, 0.07 (1.27) ng/mL in coeliac disease, and 1.73 (2.17) ng/mL in ulcerative colitis" using the CUSABIO assay. Unfortunately, when compared with the other commercial assay (the Immundiagnostik assay), there was apparently little relationship observed between the two when it came to [purported] zonulin levels. And things didn't get any better when for example we are told that "2 of 19 participants who were zonulin non-producers had levels detected by CUSABIO assay."

Various other experiments were carried out and reported on in the Ajamian paper. These included attempts to find out what else might be being picked up by those ELISA assays. Unfortunately, even with the notable analytical prowess of something like mass spectrometry, no definitive compound(s) emerged. Something called complement C3 is discussed, as are other potential matches: "haptoglobin, and albumin." But again unfortunately: "neither complement C3 nor haptoglobin, despite both being candidate target proteins as determined by mass spectrometry, was detected by the CUSABIO assay." So we're not really any further forward when it comes to what might be being detected by such assays.

"In conclusion, the current commercial zonulin ELISA assays investigated in this study detect different proteins, neither of which was zonulin. Therefore, there can be no value of circulating concentrations in assessing intestinal mucosal barrier dysfunction and permeability until the target proteins are indeed identified." A harsh conclusion but faithful to the results observed. What this means is that the literature already published talking about zonulin levels in this, that and t'other label/diagnosis/condition (see here) need to be treated with some caution. And yes, that includes studies that have looked at zonulin levels in autism (see here) and related labels like attention-deficit hyperactivity disorder (ADHD) (see here).

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[1] Ajamian M. et al. Serum zonulin as a marker of intestinal mucosal barrier function: May not be what it seems. PLoS One. 2019;14(1):e0210728. Published 2019 Jan 14.

[2] Scheffler L. et al. Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family. Front Endocrinol (Lausanne). 2018;9:22.

Wednesday, 20 February 2019

T. gondii mentioned in the title of this post refers to Toxoplasma gondii, a parasite with something of a rather interesting profile and history (see here and see here). I've talked quite a bit on this blog about T. gondii and it's various 'associations', but of particular interest has been the suggestion of a 'connection' between T. gondii exposure and risk of psychiatric diagnoses like schizophrenia (see here).

The findings reported by Kristoffer Sølvsten Burgdorf and colleagues [1] (open-access available here) add further evidence to such a 'psychiatric' connection with their conclusion that: "exposure to T. gondii might be a contributing causal factor for developing schizophrenia." Researchers arrived at their conclusion following the examination of an intriguing initiative called the Danish Blood Donor Study (DBDS). Started in 2010, the DBDS includes records for over 100,000 patients and "contains DNA and EDTA plasma samples, consecutive for all donors returning for blood donation after enrolment." That's a lot of data. So: authors "identified all individuals in the DBDS cohort registered with psychiatric disorders, suicidal behavior, or traffic accidents (N=5,953)." Said participants were matched with 'suitable' controls (N=7,101) and stored samples were analysed for "immunoglobulin (IgG) class antibodies against T. gondii and CMV." CMV by the way, refers to cytomegalovirus. Contact with (congenital) CMV has also been talked about on this blog (see here). CMV (exposure) also shares a potential *link* with "psychiatric disorders, cognitive deficits, suicidal behavior, and traffic accidents."

Results: "Of the 11,546 studied individuals, 2,990 and 7,020 individuals, respectively, tested positive for IgG class antibodies against T. gondii (25·9%) or CMV (60·8%)." Onward: "We found that individuals with a T. gondii infection had increased odds of being diagnosed with schizophrenia disorders compared to those without infection." Because researchers were also able to access other national databases containing details on outcomes like diagnosis of a psychiatric disorder and 'attempting suicide' and cross-reference them with their participants, they were also able to look at "temporality, with pathogen exposure preceding outcome" as a factor. And when they did, that T. gondii exposure - schizophrenia association was described as "even stronger." The other data on T. gondii or CMV exposure in relation to traffic accidents or suicide attempts was not as statistically strong, and indeed nothing showed significance when temporality was taken into consideration in relation to causation. On that basis, I'm gonna leave that part of the results without further comment.

This was a good study. It drew on data from a well-defined group (those Scandinavian databases 'do it' yet again) and was able to take into account the important issue of temporality. It wasn't a perfect study - "We cannot rule out that socio-economic factors could potentially account for part or all of the observed causal effect" - and said nothing about possible mechanism(s) of effect however. That being said, I'm willing to go along with the conclusions made and the need for a lot more investigation in this area linking T. gondii exposure and subsequent risk of mental illness. In particular whether new or existing treatment methods for T. gondii *might* hold the promise of much more...

Well, yes and no. No, because things like 'psychiatric symptoms and disorders' have already been talked about with regards to older age adults with autism [2] (see here also), alongside various other 'medical comorbidity' being noted in this group (see here). But also yes, because the scale of the physical and mental health conditions identified by Bishop-Fitzpatrick & Rubenstein is quite literally jaw-dropping: "immune conditions (70.6%), cardiovascular disease (49.0%) and its risk factors (46.2%), sleep disorders (85.3%), gastrointestinal disorders (49.7%), neurologic conditions (55.9%), and psychiatric disorders (72.0%) were highly prevalent in our full sample." Said full sample consisted of "de-identified Medicaid claims data for 143 adults with a recorded autism spectrum disorder diagnosis aged 40–88 years."

Researchers also mention how 44% of their sample had an intellectual (learning) disability. This kinda accords with various other data on this topic (see here). Other observations mentioned by the authors also complement existing (peer-reviewed scientific) knowledge that: (a) intellectual (learning) disability seems to bring about an increased risk of epilepsy appearing alongside autism (see here), and (b) depression and anxiety prevalence seems to be particularly elevated in those with autism without any accompanying learning disability (see here) (assuming that depression and/or anxiety are actually being screened for in those with autism + learning disability).

What do the collected data imply? Well, screening is important. Screen and screen and screen and screen. Screen for lots of things, and if something turns up, treat / manage it. If your average Jane or Joe turned up at their Doctors office with a sleep disorder or the symptoms of cardiovascular disease, medical professionals would do something about it. If the Doctor also knew that Jane / Joe might, for example, be more likely than usual to be in receipt of certain classes of medicines that potentially elevates such risks further, they'd be even more keen to screen and intervene. So it should be the same if Joe or Jane is diagnosed with autism or an autism spectrum disorder (ASD).

I'd also suggest that such data should really be leading to a lot more questioning about why? Why do people on the autism spectrum seem to be at particularly high risk of 'immune conditions' or 'digestive disorders'? Are there potential genetic links between autism and such conditions as per the notion that 'autism genes aren't necessarily just genes for autism' (see here) or that such genes might also affect other biological systems as well as the grey-pink matter floating around the skull (see here for example)? Are there other intricate connections between such classes of conditions as per the idea that sleep problems seem to follow gut problems for some (see here)? Why? Pain, discomfort, something else? And don't even get me started on the whole 'immune system - autism' connection (see here for example) which has been known about for many, many, many years. Known about but brushed under the carpet by some.

And whilst talking about the research tag-team that is Bishop-Fitzpatrick & Rubenstein, I once again would direct you to another important paper of theirs [3] about how we need to be very careful about using the word 'comorbidity' when referring to the various mental and physical issues that are over-represented around autism. As we've seen from other research (see here and see here), the core features of autism may very well predispose to a lot more than just autism and, in that respect, this might go way beyond just comorbidity...

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[1] Bishop-Fitzpatrick L. & Rubenstein E. The physical and mental health of middle aged and older adults on the autism spectrum and the impact of intellectual disability. Research in Autism Spectrum Disorders. 2019. Jan 29.

Monday, 18 February 2019

The quote titling this post - "serum levels of certain endocannabinoids are substantially decreased in people with ASD [autism spectrum disorder]" - comes from the paper published by Adi Aran and colleagues [1]. It adds to previous study on this topic (see here) and continues a research theme from members of this authorship team where the word 'cannabis' is being discussed - in the peer-reviewed science domain - in the context of [some] autism (see here).

Distinct from the last time authors' research appeared on this blog talking about the feasibility of "Cannabidiol-Rich Cannabis" 'for autism' [2], the name of the research game this time around was to assess "the circulating levels of several endocannabinoids and delineate the correlations between their levels and disease characteristics in a large group of children with ASD and their matched controls with typical development." Researchers mention how previous studies in this area "were not designed to comprehensively characterize the involvement of the ECS [endocannabinoid system] in the pathogenesis of ASD" in quite a sweeping blow to some of the other research in this area.

Results: "Serum levels of the main endocannabinoid AEA and its structurally related compounds OEA and PEA were lower in children with ASD versus age-, gender-, and BMI [body mass index]-matched control group of typically developed children." Nothing particularly new there, as the lower levels of anandamide for example, mimic those reported by Karhson and colleagues [4]. Researchers also mentioned how their findings *might* also have some other potential: "circulating AEA, OEA, and PEA might be used to identify a biologically homogeneous subgroup of ASD, predict response to treatments and adverse reactions to medications, and assist in the development of novel drugs that target specific core symptoms of ASD." Interestingly, some of these 'options' have already been explored [5] in humans and also some animal models [6] with autism in mind.

As to the biochemical *links* between the Aran findings and indeed, the ECS more generally with autism, well, there's still a way to go to decipher them all yet. There are clues emerging [7]; clues that intersect with other important autism-relevant concepts like inflammation among other things. I note also the authors mention how their findings "support the rationale in the ongoing and emerging clinical trials of CBD [cannabidiol] in ASD" (see here) and some results to come.

Saturday, 16 February 2019

I approach the findings reported by HM Vidyashree and colleagues [1] with my typical critical eye but perhaps also with a sense of 'receptivity' to the idea that yoga training *might* be useful for some people diagnosed as being on the autism spectrum. My receptivity is there because: (a) "yoga is a safe and effective way to increase physical activity, especially strength, flexibility and balance" according to the NHS guide to yoga, and (b) putting aside any (non-testable) spirituality or the like associated with yoga use, I'd like to think that some of the aims of and techniques used in yoga are similar to that seen with some of the martial arts. As well as being a fan of the martial arts - Shotokan karate is my particular hobby - certain martial arts already have some quite positive 'history' in the context of autism in the peer-reviewed science arena (see here and see here for examples). We'll see what we'll see...

The Vidyashree paper had the aim: "to investigate the effect of yoga intervention on short-term heart rate variability (HRV) in children with ASD [autism spectrum disorder]." HRV is basically what it describes: "a measure of the variation in time between each heartbeat." That variation is controlled by something called the autonomic nervous system (ANS), which basically regulates various bodily functions typically minus conscious input from ourselves. From what I gather, a low HRV is something to be avoided; as people talk about a higher HRV being linked to better cardiovascular fitness as well as increased resilience to stress (whatever that means). You probably won't be surprised to hear that HRV has been previously talked about with autism in mind [2], albeit with a lot more investigation required (see here).

So: "50 children (38 boys and 12 girls) with ASD were recruited from Swabhimaan Trust, Palavakkam, Chennai." All were diagnosed with an autism spectrum disorder (ASD) and "were grouped into ASD with yoga intervention (n = 25) and ASD without yoga intervention group (n = 25) by simple lottery method." HRV was recorded via an ECG (electrocardiogram) on two occasions, before and after intervention/non-intervention. Said yoga intervention - in 40 minute sessions - was apparently delivered "every day in the morning" over 3 months. That's quite a few sessions...

Results: bearing in mind 10 participants and 5 participants from the yoga and non-yoga groups respectively were excluded from the data analysis side of things, a few details were observed. So: "There is a significant reduction in mean HR [heart rate]... in the ASD children after yoga intervention." As a group, the mean baseline HR for the yoga group was around 90 beats per minute. After intervention, this dropped to under 80 beats per minute. At the same time, the non-yoga group showed an increase in their mean heart rate over the same period. Other results, more technical results, are also included in the Vidyashree paper which I believe translate into measuring HRV [3]. I can't pretend to know all the hows-and-whys of those results, but with a cursory reading of the literature in this area, am willing to go along with the authors' conclusions that results: "showed significant improvement" coinciding with the yoga intervention.

Obviously a lot more study is required in this area before any grand claims about yoga or anything else are made in the context of autism. The Vidyashree results were firmly focused on HRV following yoga and said nothing about how yoga may/may not have affected some of the behavioural profiles associated with autism for example. Likewise, all the stuff about lower HRV being linked to greater resilience to something like stress have not been fully analysed in the context of the current results either. All of this comes alongside the methodological issues that accompany the Vidyashree: an open-trial, yoga vs. no yoga, etc.

But I still remain interested in the potential of something like yoga in many contexts including that related to autism...

Friday, 15 February 2019

The quote forming part of the title of today's post - "The regression group was significantly more functionally impaired..." - comes from the findings reported by Lucy Thompson and colleagues [1] (open-access available here). It continues something of an important theme in autism research circles whereby regression, as in a regression of previously acquired skills, is being seen as important not just for a few but for many (see here).

There were a few aims to the Thompson study such as establishing "the relative prevalence of regression in autism" and "possible predictors, mediators and moderators of regression in autism, including pre- and perinatal factors." The data for the study were derived from "two community-based cohorts" in Sweden totalling just over 300 participants (children) diagnosed with an autism spectrum disorder (ASD) who were observed over two different time points (T1 and T2 2 years later). Another important detail is mentioned by Thompson et al: "Given the lack of previous systematic representative studies in the field, our study sets out to be descriptive rather than hypothesis-driven." Figures and details on regression in the cohort(s) were obtained via specific questioning on this topic "defined as loss of expressive language skills (loss of 5 or more words that had been used communicatively) in connection with the onset of autism." This data was also combined with other medical records information to determine 'consistency'.

Results: "Just over 20% (62/303) of the combined sample of children had regressive autism." That's 1 in 5 children with autism experiencing some kind of regression in relation to language skills. When looking at those who regressed (n=62) compared with those with no regression (n=241), a few details emerged: "Those with regressive autism had a younger age when they first walked... had a more severe language impairment at T1... and more often intellectual disability... [and] lower mean VAB [Vineland Adaptive Behaviour Scales-II] scores." Also: "Severity of autism was higher in the regressive group, with a higher proportion of children with autism... (as opposed to autistic-like condition)."

This is important data. It kinda tallies with other studies of regression accompanying autism suggesting that those who regress tend to have a more 'severe' form of autism with accompanying learning (intellectual) disability. The diagnostic issues - as in more likely to be diagnosed with Kanner's autism rather than other diagnoses - similarly ties in with other findings.

Caveats? Well, a few: "We have chosen to focus on language regression specifically (rather than social, play or motor regression) as communication is by far the most common skill to be lost or diminished in regressive autism." That being said, regression accompanying autism seems to take many, many forms and does not always just mean a loss or partial loss of vocal communication (see here).

Also: "There was also a similar level of maternal disease in pregnancy in the regressive and non-regressive groups, suggesting that prenatal exposure via maternal disease does not seem to be a key feature in the development of regressive autism." I have to question why the authors stuck to looking at just pre- and perinatal factors as possibly being *linked* to regression when regression is likely to occur quite some time after such a developmental window. Surely it would have made more sense to ask a few further questions about the timing of regression - "The average age at regression was 20.13 months... with 54 children (88.5%) showing regression by the age of 24 months" - and whether one or more event might have proceeded such regression in a similar time frame. Y'know whether infection might be a feature (see here and see here for examples) or whether other events might require further investigation (see here). I know this might take such research down some uncomfortable paths, but temporality is surely an important factor for some regression in some cases of autism? Or am I being too unreasonable?

I might also advance the idea that the time to start asking questions about the biology of regression accompanying autism is fast approaching. We've already had some clues in the recent (at the time of writing) peer-reviewed research literature (see here) but lots more needs to be done in this area. Are there important genetic and/or epigenetic variables to consider? Do mitochondrial issues play a role in some regressive autism (see here)? We just don't know enough yet. And yes, this does mean also asking about whether regression in behaviour or cognitive skills was also accompanied by any changes to somatic variables too (see here).

And then there is another question to ask/answer: does regression mean that certain 'therapeutic' options might be particularly useful? I'm thinking back to some research a few years back talking about corticosterioid therapy *potentially* being indicated for some cases of regressive autism (see here). No, I'm not making any medical or clinical claims or giving any advice on such an issue. Merely mentioning that regressive autism needs to be more of a research priority than it currently is. To quote Thompson and colleagues again: "Children with a regressive developmental trajectory, with or without autism, always need a careful neuropediatric work-up to investigate possible neurological disorders that may lead to developmental regression, taking into account possible treatable conditions." Who would argue with that?

Thursday, 14 February 2019

Building on other reviews of the peer-reviewed science literature looking at the intestinal microbiota in relation to autism (see here), the paper published by Feitong Liu and colleagues [1] provides an updated 'where we're at' position in relation to the "potential evidence for the characteristic dysbiosis of gut microbiota in ASD [autism spectrum disorder] patients compared with healthy controls (HCs)." Just before you say anything, those are the authors words not mine; I'm not a fan of the word 'patients' nor use of the term 'healthy control' to denote not autism - not autistic, but there you go.

Language use aside, the Liu paper covers quite a lot of the peer-reviewed science talking about gut bacteria and autism up to March 2018. Their systematic review took in data from 16 studies - human studies "that compared the composition of gut microbiota in ASD patients and HCs using culture-independent techniques." Researchers had also previously registered their intention to conduct this review as per their PROSPERO entry (see here).

So what did their systematic review reveal? Well, they talked about how most studies looked at the intestinal microbiota via the examination of stool samples, although a couple relied on gut biopsy samples instead. Coincidentally, I spotted a bit of an error in the Liu paper in relation to their study reference numbering in one of the results sections, and how the Luna study (see here) and Williams study (see here) which relied on biopsy samples were replaced by other 'stool as a sample media' studies in the Liu write-up. It's only a small point and doesn't detract from the paper overall. The included studies also covered various different populations in a geographic sense as well as taking into account a mix of participants (with autism) in terms of the presence of gastrointestinal (GI) issues and the use of 'special' diets. Indeed, we are told that: "As restricted diet is very common in ASD patients, we tried to extract the information of eating habit in ASD and control group." Yes it is common, and yes it can have sometimes very negative effects (see here). Finally, all the studies included for review were "identified and assessed as medium (6–7) to high (8) quality" suggesting that the data were pretty reliable in a methodological sense.

Some key points emerged: "Overall, the changed structure of gut bacterial community in terms of β-diversity was observed coherently in ASD patients compared with HCs." Beta-diversity basically translates into 'between samples diversity' and in this case represents autism vs. not-autism controls. Out of the 16 studies included in their systematic review, Liu et al reported that "ten studies analyzed β-diversity (unweighted UniFrac distance, weighted UniFrac distances, and Bray-Curtis)." Six of those 10 studies "consistently reported that the microbiota of ASD patients clustered significantly apart from that of HCs." Ergo, there is evidence - some evidence - that the gut microbiome is significantly 'different' in autism compared with not-autism in a group sense. Some evidence at least.

Also: "Consistently, ASD patients had elevated abundance of Proteobacteria rather than HCs. In addition, Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter were consistently decreased, while Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium were increased in ASD patients relative to HCs." Bear also in mind that Liu et al talked about various other bacterial species that were, in individual studies, elevated or depressed in the groups with autism, and how important such information might be. Such bacterial changes in terms of diversity or individual species predominating might also have knock-on effects as a result of the different chemical messages that different bacteria produce. One example: "Bacteroides is an abundant genus at all ages, from infants to adults. It is the main producer of propionate in the gut, and the abundance of propionate in feces correlates strongly with the abundance of Bacteroides." It probably won't surprise you to hear that propionic acid (propionate) has also got some research history when it comes to autism (see here) and indeed, with caveats, continues to do so [2]. Other examples are included in the Liu paper, including the 'chemical of the moment', butyrate (butyric acid) (see here). This complements other recently published research [3] too. And let's not forget how such bacteria and their chemical messaging also has some important 'effects' on things like gut barrier function and gut immune function, as part of the 'new triad' when it comes to autism and the gut (see here).

"Microbiome reconstitution could be a potential therapy to ASD patients in future." That's another topic raised in the Liu study on how "remodeling gut microbiota with diet, antibiotics, prebiotics, probiotics, and FMT [fecal microbiota transplant]" could be an option. Actually the future is now, as a quick scour of the autism research literature shows that some of these options are already being / have been investigated (see here and see here for examples). We do need a lot more information on the hows-and-whys of such therapeutic options; importantly covering safety, effectiveness and maybe highlighting the possible mechanisms involved, but there is already existing literature in this area.

As well as highlighting some of the shortcomings of the current research literature discussing the intestinal microbiota and autism, the Liu study provides a nice overview of this topic as things currently (up to March 2018) stand. Whether such information can eventually be 'manipulated' to improve things like quality of life in the context of autism remains to be seen...

Wednesday, 13 February 2019

This is a difficult post to write. It's difficult because it covers several topics which are increasingly being *linked* together: autism, the school experience, behavioural problems and aggression, school exclusion and onward 'engaging' with the criminal justice system. Such topics aren't exactly great PR for autism as a diagnosis or label, but do need to be more openly talked about and researched. Useful and productive lives are potentially being wasted (and already vulnerable lives at that).

I was brought to write this post by an opinion piece published in The Conversation titled: "Too many children with autism are let down by schools and end up in prison" [1] by Chrissie Rogers. The author details her research talking to mothers with sons diagnosed with autism or autism spectrum disorder (ASD) who have been and/or are involved with the criminal justice system. Looking at her biography at the University of Bradford, this research looks like its been (partly) published (see here). Having said that, comments left following publication of the Conversation piece, hint that there might be more to come from the author too.

"Mothers in my research talked to me about how their sons were “different”. They were violent to other children and teachers as well as their own families." Reiterating that discussions on this topic don't make for great PR when it comes to autism, such words complement something that has recently been legally enshrined in English law: "aggressive behaviour is not a choice for children with autism." That ruling (see here), based on the case of the unlawful exclusion from school of an autistic boy "after he hit a teaching assistant with a ruler, punched her and pulled her hair" has some potentially far-reaching consequences. It tells us that (a) such behaviour is "akin to a spasmodic reflex" and also that (b) such behaviour should be always be investigated as a 'sign of unmet need'. By saying all that, please don't assume that I condone such behaviour or am trying to pass/move on any blame; I merely suggest that there are often complicated processes behind such actions (see here and see here) which one needs to fully analyse and take into account.

"All the mothers told me they felt something was “not quite right” with their child. And because the support was not forthcoming at school, this negative behaviour escalated and then as these boys got older, they ended up in prison." I think we have to be a little bit careful with some of the things that Rogers discusses here. Yes, it's perfectly sensible to imply that schools 'just excluding pupils' does little to nothing to help efforts to address such 'negative behaviour'; indeed, such actions probably add to a downward spiral, including impacting on the self-esteem of the child concerned. But I'm not altogether convinced that schools that exclude should shoulder such blame alone. Although school exclusion is quite a prominent historical feature of the prison population for example (see here), there are lots of other variables to potentially consider as exerting an important effect on offending behaviour too. And bear also in mind the concept of 'vulnerability' when it comes to autism (see here and see here), and what this can sometimes/often mean in relation to specific types of offending behaviour. What I'm trying to say is that simple correlations or connections are often not entirely correct correlations.

"If more support and intervention in the education system was to occur before the police got involved, then these young people would be less likely to end up incarcerated and at the bottom of a human hierarchy." Again I'm slightly cautious about such sweeping statements being made despite supporting the idea that the educational sector should be the more influential factor over the criminal justice system. 'Support and intervention' is quite a nebulous term and could cover a lot of ground. Although provisions like an EHCP (education, health and care plan) make it (financially) easier for schools and the like to provide additional support, the idea that there is a quantitative correlation between more support and intervention and better outcomes needs to be treated quite cautiously. Indeed, going back to that legal ruling about aggressive behaviour not being a choice for children with autism, the focus really needs to be dual-purpose, examining questions like 'what are the biological and social reason(s) and circumstance(s) for aggression?', and 'what mechanisms can be put in place to minimise such aggressive acts and/or their effects?' I also noted that puberty is mentioned as being part of the behavioural 'mix' in the Rogers article. It strikes me that this is a good place to start when examining the impact that biology in particular can have in relation to the presentation of aggression in the context of autism (see here).

I know lots of people talk about how our one-size-fits-all education system is not necessarily fit for purpose for every child. I wouldn't disagree with such sentiments. Rogers also points out that the drive towards 'inclusive education' whereby education in mainstream schools is becoming the default option for anyone and everyone is also not seemingly serving many children very well. Again, I wouldn't disagree (see here). What I would however say is that focusing in on schools and their actions as 'being the problem' strikes me as being too broad and sweeping a generalisation to make. Indeed it's revealing that Rogers mentions how the mums she interviewed talked about "a lack of support, lack of access to professional help and an overwhelming lack of understanding about their son’s disability, and the impact this had on their lives." Such words speak volumes about how school is but one piece of a larger puzzle that needs a lot more investigation and resources to be directed towards it when it comes to autism, aggression, school exclusion and any subsequent heightened risk of contact with the criminal justice system.

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[1] Rogers C. Too many children with autism are let down by schools and end up in prison. The Conversation. 2019. Jan 24.

ABOUT AUTISM SPECTRUM CONDITIONS

Autism or autism spectrum conditions describe several presentations characterised by core issues with social affect and stereotyped or repetitive actions. Diagnosis is made by observation and analysis of developmental history. These are heterogeneous conditions which can carry various co-morbidities and whilst described as life-long are affected by age and maturation. Autism means different things to different people. To some it means a need for life-long support. To others it is part of the varied tapestry of humanity. To all it means a need to foster a welcoming society with appropriate support and opportunities.